Much of the work on inhalation anthrax has exclusively focused on the exotoxins. Our recent studies indicate that the peptidoglycan component of the B. anthracis cell wall induces the production of inflammatory cytokines and chemokines. The production of the cytokines and chemokines is exclusively from peripheral blood monocytes; lymphocytes and neutrophils do not respond. We have preliminary and on-going structural work to chemically characterize B. anthracis peptidoglycan. We have novel tools to identify the currently unknown extracellular receptor for Gram-positive peptidoglycan and to understand the signaling events induced by the receptor and causing the changes in monocyte biology. Additionally, we have new data indicating that peptidoglycan induces monocyte apoptosis in a subpopulation distinct from the monocytes producing inflammatory cytokines. We present an experimental plan to identify the mechanism of peptidoglycan-triggered apoptosis. The monocyte apoptosis might contribute to the high mortality of B. anthracis and possibly of other Gram-positive pathogens by eliminating an important component of the innate immune system. We will test this possibility by challenging rodents and non-human primates with B. anthracis peptidoglycan and measuring monocyte levels.